Nanobodies (Nbs) hold great promise as next-generation cancer immunotherapies, but their efficacy is hindered by their poor pharmacokinetics and the inability to trigger Fc-mediated immune killing functions. To address these limitations, we designed and synthesized rhamnolipid-modified Nbs as a type of antibody-recruiting molecule by site-specifically conjugating EGFR-targeting Nb 7D12 to a series of rhamnolipid derivatives, and their biological profiles were evaluated in vitro and in vivo. Investigation of the structure-activity relationship revealed that the number of rhamnose (Rha) units and the length of the PEG linker in the conjugates affected anti-tumor activities. Conjugate R5, which contained two Rha units and a PEG₂ linker, exhibited the most potent antibody-dependent cell-mediated phagocytosis (ADCP) and complement-dependent cytotoxicity (CDC) activities. In vivo, R5 had a significantly longer half-life because of its ability to bind to serum albumin and endogenous anti-Rha antibodies, and it demonstrated potent in vivo antitumor activity in a xenograft mouse model of A431 tumor. Our findings highlight the potential of rhamnolipidation as a strategy to enhance the efficacy of Nbs in cancer immunotherapy and provide a cost-effective platform for improving the therapeutic efficiency of Nbs.

09 Jan 2025·The Journal of Physical Chemistry Letters

Evaluating the Synergistic Effects of Multi-Epitope Nanobodies on BA.2.86 Variant Immune Escape

Article

Author: Zhang, Enhao ; Zhang, John Z. H. ; Xu, Xiaole ; Luo, Song ; Duan, Lili ; Liu, Jinxin ; Liang, Houde

Addressing the frequent emergence of SARS-CoV-2 mutant strains requires therapeutic approaches with innovative neutralization mechanisms. The targeting of multivalent nanobodies can enhance potency and reduce the risk of viral escape, positioning them as promising drug candidates. Here, the synergistic mechanisms of the two types of nanobodies are investigated deeply. Our research revealed that the Fu2-1-Fu2-2 system exhibited significant synergy, whereas the Sb#15-Sb#68 system demonstrated antagonism, in which entropy was the dominant contributor to antagonism. Conformational analysis further demonstrated that the presence of a monomeric nanobody influenced the flexibility of residues near other epitopes, thereby affecting the overall synergy of the systems. Moreover, we identified that changes in the hydrogen bond network and the charge of residues played a critical role in the binding between nanobodies and spike. We hope this study will provide novel insights into the development of multivalent nanobody combinations.

06 Jan 2025·Nucleic Acids Research

PLAbDab-nano: a database of camelid and shark nanobodies from patents and literature

Article

Author: Deane, Charlotte M ; Greenshields-Watson, Alexander ; Agarwal, Parth ; Boyles, Fergus ; Hummer, Alissa ; Gordon, Gemma L ; Lujan Hernandez, Ana G ; Wong, Ashley

AbstractNanobodies are essential proteins of the adaptive immune systems of camelid and shark species, complementing conventional antibodies. Properties such as their relatively small size, solubility and high thermostability make VHH (variable heavy domain of the heavy chain) and VNAR (variable new antigen receptor) modalities a promising therapeutic format and a valuable resource for a wide range of biological applications. The volume of academic literature and patents related to nanobodies has risen significantly over the past decade. Here, we present PLAbDab-nano, a nanobody complement to the Patent and Literature Antibody Database (PLAbDab). PLAbDab-nano is a self-updating, searchable repository containing ∼5000 annotated VHH and VNAR sequences. We describe the methods used to curate the entries in PLAbDab-nano, and highlight how PLAbDab-nano could be used to design diverse libraries, as well as find sequences similar to known patented or therapeutic entries. PLAbDab-nano is freely available as a searchable web server (https://opig.stats.ox.ac.uk/webapps/plabdab-nano/).

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	BE	VIB-VUB Center for Structural Biology	03 Sep 2024

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